Nitroimidazoles



United States Patent 3,299,090 NITROIMIDAZOLES Dale R. Holt, Cranford,and David W. Henry, Plainfield, N..I., assignors to Merck & Co., Inc.,Rahway, Ni, a corporation of New Jersey No Drawing. Filed Mar. 27, 1964,Ser. No. 355,428 6 Qlaims. (Cl. 260--3tl9) This invention relates to newnitroimidazoles. More particularly, it is concerned withZ-(a-aminoalkyD-nitmimidazoles. Still more specifically, it is concernedwith 1-substituted-Z-aminoalkyl-S-nitroimidazoles, withl-substiututed-2-substituted-aminoalkyl-5 nitroimidazoles and withmethods for the chemical synthesis of such new compounds. It relatesfurther to the use of such substances against parasitic infections andto anti-parasiticcompositions containing such substances as activeingredients. It is further concerned with novel Zhaloalkyl imidazolesuseful as intermediates in the synthesis of such aminoalkyl andsubstituted-aminoalkyl imidazoles.

Although various nitroimidazole compounds have been described as usefulagainst certain parasitic diseases, in particular against the poultrydisease histomoniasis and the protozoal infection trichomoniasis, thesearch has continued for new, more active and less toxic agents for thetreatment of these diseases.

Trichomoniasis is a disease caused by the protozoan parasite Trichomonasvaginalis. T. vaginalis primarily infests the human vagina and is theetiological agent of a very troublesome and prevalent form of vaginalinfestation known as T. vaginalis vagim'tis, The drugs heretoforecommercially available for treating this condition have certainlimitations and disadvantages. In particular, there has been a need foran an-ti-trichomonal substance that is effective when administeredorally as well as topically.

Histomoniasis is a poultry disease caused by the protozoan parasiteHistomonas meleagridis. This disease, which affects turkeys, is alsoknown as turkey blackhead or enterohepatitis. It is a serious economicproblem to the turkey-raising industry since it spreads rapidly inturkey fiocks and the mortality rate may be as high as 80%. Thecompounds now commercially available for treating turkey blackhead areof benefit, but none of them has proven to be entirely satisfactory.Among the disadvantages are development of resistant strains of theinfecting organism, and undesired side effects when fed to the birds atthe levels required to treat the disease.

It is an object of the present invention to provide a new class ofantitrichomonal and antihistomonal agents, It is a further object toprovide a new and novel class of nitroimidazoles having a significantdegree of antiprotozoal activity. Another object is provision ofl-substituted-S- nitroimidazoles having an ot-aminoalkyl orot-substitutedaminoalkyl group at the 2-position of the imidazole ring.An additional and more specific object is provision of 2aminomethyl-S-nitroimidazoles andZ-substituted-aminomethyl-S-nitroimidazoles having a lower alkyl,hydroxyloweralkyl or acyloXyloweralkyl radical at the 1-position of theimidazole ring. Another object of the invention is provision of methodsfor making such 1,2-disubstituted- S-nitroimidazoles. A still furtherobject is provision of new 2-halomethyl-S-nitroimidazoles having aloweralkyl, hydroxyloweralkyl or acyloxyloweralkyl radical at the1-position, which compounds are key intermediates in synthesizing saidZ-aminomethyl and 2-substituted-arninomethyl imidazoles. An additionalobject is provision of antitrichomonal and antihistomonal compositionscontaining the imidazole compounds of this invention as activeingredients. A still further object is provision of methods for treatingand/or preventing trichomoniasis and histo- Patented Jan. 17, 1967 I I/R2 l H H /R2 OEN cum and om CN N N l a, A m R a R represents aloweralkyl radical examples of which are methyl, ethyl, propyl, butyland amyl, or a radical of the structure -(CH OY, where n is a wholeinteger having a value of 2, 3 or 4, and Y is hydrogen or an acyl group,such as a lower alkanoyl radical, e.g., acetyl, propionyl or butyroyl orbenzoyl. Y may further be a substituted benzoyl radical such as p-haloor p-nitrobenzoyl. In the preferred compounds of the invention, R is amethyl or a 2-hydroxyethyl radical. Each of R and A in Formula II aboverepresents loweralkyl, preferably methyl. R and A may be the same ordifferent.

At the 2-position of the imidazole ring of the compounds of thisinvention there is present an aminomethyl or substituted aminomethylgroup, as shown in Formula I. Alternatively, the 2-position may containan a-aminoalkyl or u-substituted-aminoalkyl radical of at least twocarbon atoms, i.e., the compounds represented by Formula II. In eithercase, the end compounds of the invention have an amino orsubstituted-amino group or an alkyl group in the 2-position.

The moiety NR R in the above formulas represents amino, loweralkylaminoor di-loweralkylamino such as methylamino, dimethylamino, ethylamino,isopropylamino, dibu-tylamino and diethylamino; arylamino such asanilino, naphthylamino, p-nitroanilino or p-methylanilino; aralkyla minosuch as 'benzylamino; loweralkenylamino, e.g., allyla-mino ormethallylamino; cycloalkylamino, examples of which are cyclopentylamino,cyclopropylamino and cyclohexylamino; acylamino, and particularlyloweralkanoylamino such as acetylamino, propionylarnino andbutyroylamino, or benzoylamino. Alternatively,

represents a five or six-membered nitrogen containing heterocyclic ringwherein the nitrogen atom of NR R is part of the he-terocyclic ring andR and R together represent the rest of the ring. Thus, NR R representsradicals such as l-morpholinyl, l-thia morp-holinyl, piperidyl,pyrrolidinyl, piperazinyl, imidazolyl, triazolyl, pyrryl, pyrazolyl,pyrrolidonyl, a-pyridonyl of the strucq -pyridonyl of the formulaS-pyrazolonyl of the formula and Z-irnidazolonyl of the formula In allof the above ring systems a ring nitrogen atom is attached directly tothe a-carbon in the 2-position of the -nitroimidazole. The aboveenumeration of suitable heterocyclic rings in the meaning of NR R isintended to be exemplary and not an exhaustively complete list. In orderto prepare the compounds of Formulas I and II by the process describedhereinafter, the nitrogen containing reactant must have at least onereactive hydrogen on the nitrogen atom. Thus, for example, an aromaticsix-membered nitrogen-containing heterocycle such as pyridine will notreact in the process of the invention, and --NR R does not include suchsubstances.

Also within the purview of the invention are acid addition salts of the1-substituted-Z-aminomethyl-S-nitroimidazoles of Formulas I and IIabove. The preferred salts are the relatively non-toxic mineral acidsalts such as the hydrochlorides, sulfates, and nitrates. Organic acidsalts, such as the acetate, citrate, tartrate, oxalate and the like, mayalso be prepared of those compounds in which the NR R group is not anacyl type substituent. In some cases, it may be preferred to employthese products in the salt rather than the free base form in treatingthe parasitic diseases previously mentioned.

The compounds of the present invention are prepared from1-su'bstituted-2hydroxymethyl-S-nitroimidazole ac cording to a processwhich comprises broadly the reaction of said Z-hydroxymethyl imidazolewith a halogenating agent to obtain a 1-substituted-2-halomethy1-5-nitroimidazole, and reaction of such halomethyl imidazole with an amineto produce a 1-substituted-Z-substh tuted aminomethyl-S-nitroimidazole.This process is employed for the preparation of most of the aminomethyl(and ot-aminoalkyl) compounds of the invention. Some modifications,which will be discussed hereinafter, are preferred in the second step ofthis synthesis for preparation of1-substituted-2-aminomethyl-S-nitroimidazole itself (where NR R in theabove formula represents NH and of the aralkylaminomethyl imidazolessuch as the 1-substituted-2-benzylaminomethyl-S-nitroimidazole.

According to the first reaction of this invention l-loweralkyl-2(a-hydroxy) loweralkyl-S nitroimidazole or 1-(acyloxyalkyl)-2-hydroxymethyl-S-nitroimidazole is intimately contactedwith a halogenating agent in order to convert the Z-hydroxymethylsubstituent to a Z-halomethyl radical. It is preferred to form eitherthe chloromethyl, bromomethyl or iodomethyl imidazole by treating thestarting material with the appropriate halogenating agent. When thestarting material contains a hydroxyalkyl group at the 1-position, thisgroup is blocked by acylation prior to the halogenation step in order toprevent undesired side reaction. This is accomplished by converting thehydroxyalkyl moiety to a benzoyloxy or lower alkanoyloxy derivative viatreatment with an acylating agent. This halogenation reaction and thesubsequent treatment of the 1-substituted-Z-haloalkyl-S-nitroimidazolewith an amine is carried out in the same fashion on compounds of bothFormulas I and II above. For the sake of simplicity,

the ensuing description of these processes will be directed primarily tothe preparation of substances of Formula I, although it will beunderstood that it applies as Well to the haloalkyl and aminoalkylimidazoles of Formula II.

Suitable chlorinating agents which may be used satisfactorily in thisreaction are thionyl chloride, aqueous concentrated hydrogen chloride,phosphorous oxychloride, phosphorous pentachloride and phosphoroustrichloride. The preferred brominating agents are aqueous concentratedhydrogen bromide, thionyl bromide or phosphorous tribromide. Hydrogeniodide is conveniently employed as halogenating agent to make the2-iodomethyl compounds. This aspect of the invention is not limited tothese particular halogenating agents and other equivalent halogenatingagents may be used if desired. The halogenation is brought about byintimately contacting the lsubstituted 2 hydroxymethyl S-nitroimidazoleand the halogenating agent in a suitable reaction medium. An excess ofhalogenating agent is generally used, and where such reagents are liquidand easily removed at the completion of the reaction, the excesshalogenating agent itself may serve as the solvent medium. This isconvenient, for example, when thionyl chloride is used as the reagent.It is generally preferred, however, to carry out the reaction in anorganic solvent which is inert under the reaction conditions. Examplesof such solvents are aromatic hydrocarbons such as benzene, toluene,xylene, and the like, chloroform, dimethoxyethane and methylenechloride. The time and temperature of the reaction are not critical andhalogenation may be carried out at room temperature or at elevatedtemperature. Reaction temperatures of from about room temperature toabout C. give very satisfactory results and under these conditions thehalogenation is essentially complete in from about 15 minutes to 3hours. The 1 substituted 2 halomethyl 5 nitroimidazole is formed as anacid addition salt, i.e. as the hydrochloride or hydrobromide. The acidaddition salts of these nitrolimidazoles are much more highlycrystalline than are the free bases and for this reason it is preferredto isolate the salts. The imidazole free base is obtained by treating anaqueous solution of the salt with base and extracting the resultingimidazole base into an organic solvent such as chloroform. If desired,those 2-halomethyl-S-nitromidazoles having a l-acryloxyalkyl radical maybe hydrolyzed with acid to the corresponding l-hydroxyalkyl compoundsalthough, as previously stated, it is preferred to carry out the aminereaction prior to the acid hydrolysis.

Representative examples of Z-haloalkyl-imidazoles prO- vided by thisinvention are 1-methyl-2-bromomethyl-5- nitroimidazole,1-ethyl-2-iodomethyl-S-nitromidazole, 1-methyl-2-(a-chloroethyl)-5-nitroimidazole,l-(fi-acetoxyethyl)-2-chloromethyl-S-nitroimidazole,l-propyl-Z-chloromethyl-S-nitroimidazole, and l-(y-benzoyloxypropyn-2-bromomethyl-S-nitroimidazole.

The -1-substituted-2-halomethyl-S-nitroimidazole compounds obtained asdescribed above are converted to the corresponding2-substituted-aminomethyl imidazoles by treatment with a primary orsecondary amine:

| R R R 3 III a In the above formula X represents a halogen having anatomic Weight greater than 35, i.e. chloro, iodo or bromo, R representslower alkyl or (CH ),,OY, where n is 2-4 and Y is hydrogen or acyl; andNR R is as previously defined except that at least one of R and R isother than hydrogen. In a similar manner, compounds of Formula II aboveare obtained from the corresponding 2-(a-haloalkyl)-imidazole.

This reaction is brought about by intimately contacting the2-halomethyl-5-nitroimidazole with an excess of a primary or secondaryamine. As will be clear to those skilled in this art, the particularsubstituted-aminomethyl- S-nitroimidazole produced is directly dependenton the amine employed as a reactant. It is preferred to employ a molarexcess of primary or secondary amine for reaction with the halomethylimidazole. At least a 2:1 molar ratio of amine to halomethyl imidazoleis used for best results in this process, and in many cases molar ratiosof up to 15:1 are desirable. When thel-substituted-Z-halomethyl-S-nitroimidazole is charged to the reactionas an acid addition salt instead of the free base, additional amine isrequired to neutralize the acid salt, and the amount of amine reactantis increased appropriately.

The process is carried out in a suitable solvent medium. It is preferredto employ an organic solvent that is nonreactive with either thehalomethyl imidazole or the amine reactants. Examples of suitablesolvents are the aromatic hydrocarbons such as benzene, toluene orxylene, diloweralkyl amides such as dimethylformamide ordimethylacetamide, a lower alkanol, e.g. methanol, ethanol orisopropanol, an aqueous lower alkanol, chloroform, acetonitrile or aketone such as acetone, methylethyl ketone or methyl isobutyl ketone. Inthose cases where the amine reactant is liquid at the reactiontemperature, an excess of such amine can serve as the solvent medium.

The reaction time and temperature are not critical features of theprocess except to the extent that it is convenient, and preferred, thatthe temperature be one at which the reactants are liquids. In the caseof low boiling amines such as methylamine and dimethylamine, thereaction is generally carried out in the cold. However, with mostprimary and secondary amines elevated temperatures of up to about 150 C.are employed since the reaction rate is thereby increased. Formation ofthe l substituted-2-su'bstituted-aminomethyl-S-nitroimidazole compoundstakes place rapidly, and in most cases the reaction is substantiallycomplete in from /2 to 2 hours, although longer times may be utilized ifdesired.

The resulting imidazole may be recovered by techniques known to thoseskilled in this art. Where the product is soluble in the reactionmedium, the solvent and unreacted excess amine may be distilled off, thedesired imidazole extracted into a suitable non-aqueous solvent such aschloroform or ethyl acetate, and then recovered in substantially pureform by removal of the solvent by distillation.

Representative examples ofl-substituted-Z-(oz-substituted-arnino)-alkyl-5-nitroimidazoles obtainedin this fashion by the reaction of al-sllbStitIltfid-Z-(or-hillOEllkYD-S-IlitIO- imidazole with a primary orsecondary amine are 1-methyl-Z-anilinomethyl-S-nitroimidazole,

1-methyl-2-morpholinomethyl-S-nitroimidazole,

l-methyl-2'diethylaminomethyl-5-nitroimidazole,

l-ethyl-2-ethylaminomethyl-5-nitroimidazole,

l-propyl-Z-cyclohexylaminomethyl-S-nitroimidazole,

l-methyl-Z-allylaminomethyl-S -nitroimidazole,

1-'met'hyl-2-( l-imidazolylmethyl -5-nitroimidazo le,

l-methyl-Z- fl-ethoxyethyl) -aminomethyl-S-nitroimidazole,

1- Z-aoetoxyethyl) -2-mor-pholinomethyl5 nitroimidazole,

1- Z-hydroxyethyl) -2-morpholinomethyl-5- nitroi-midazole,

l-methyl-Z- a-rnorpholinoethyl -5-nitroim ida zole,

N-( 1 -methyl-5 -nitro-2-imidazolylmethyl pyrrolidone,

N-( 1-ethy-l-5-nitro-Z-imidazolylmethyl -a-pyridone,

N-( l-methyl-S -nitro-Z-imidazolylmethyl) -pyrazolone,

N-( 1-propyl-5-nitro-2-imidazolylmethyl)-kojic acid,

N-( 1-methyl-5-nitro-2-imidazolylmethyl) -thiazolone,

1- 3 -acetoxypropyl) -2.-methylaminomethyl-5- nitroimidazole,

l- 2-benzoyloxyethyl) -2-allylaminomethyl-5 nitroimidazole,

l- Z-acetoxyethyl) -2- u-anilinoethyl -5 nitroimidazole, and

l-methyl-Z-thiamorpholinomethyl-S-nitroimi dazole,

The 1-acyl0xyalkyl-2-substitutedaminomethyl-S nitroimidazoles arehydrolyzed to the corresponding l-(hydroxyalkyl)-imidazoles by treatmentwith a dilute mineral acid such as hydrochloric or sulfuric acid.

The reaction of 1-substituted-2-halomethyl-S-nitroimidazole with ammoniais not a satisfactory one. For

this reason, the 1-substituted-2-aminoalkyl-S-nitroimidazoles of theformulas it t.

where R, R and A are as previously defined, are prepared from thecorresponding Z-haloalkylimidazoles by reacting the1substituted-Z-ha1oalkyl-S-nitroimidazole with an alkali metalphthalimide to produce l-substituted-Z-phthalimidoalkyl-S-nitroimidazole, and treating this latter substancewith hydrazine to form the l-substituted-2- aminoalkyl-S-nitroimidazole.Reaction of the Z-haloimidazole with alkali metal phthalimide isconveniently brought about in a solvent medium inert under the reactionconditions. Di methylsulfoxide, dimethylformamide and dimethylacetamideare examples of suitable solvents. Good results are obtained byintimately contacting the reactants in the solvent at temperatures ofabout 20-75" C. for up to 2 hours. In most cases the desired product,such as 1-methyl-2-phthalimidomethyl-5-nitroimidazole, l-methyl-2-(a-phthalimidoethyl) -5-nitroimidazole, or 1-(2-acetoxyethyl)-2-phthalimidomethyl-5 nitroimi dazole precipitatesdirectly from the reaction mixture. The succeeding hydrazine reaction isconveniently brought about by intimately contacting theZ-phthalimidoalkyl imidazole and hydrazine at elevated temperatures offrom 40100 C. in a non-reactive solvent that dissolves both reactants.Lower alkanols and aqueous dimethylformamide are examples of goodsolvents. In most cases the desired product can .be crystallizeddirectly from the reaction solvent. When this is not satisfactory, thesolvent is removed and the imidazole purified by known techniques. Inthis way,

l-methyl-2-aminomethyl-5 -nitroimidazole, 1ethyl-2-aminomethyl-5-nitroimidazole,

l- Z-acetoxyethyl -2-aminomethyl-Smitroimid azole,

l- (Z-hydroxyethyl -2-aminomethyl-5-nitroimidazole, and l-methyl-Z- u-aminoethyl -5 -nitroimidazole are produced in good yield.

The 1-substituted-2-aralkylaminomethyl-S nitroimidazole compounds of theinvention are preferably made according to a process different from thatpreviously described for the other 2-substituted-aminomethyl imidazolessince the primary amines such as benzylamine and nuolearly substitutedbenzylamines do not on reaction with the Z-halomethyl-S-nitroimidazolesgive high yields of the desired Z-aralkylaminomethyl-S-nitroimidazoles.It has been found that such substances may be obtained from 1-lOWCIalkYl-Z-(a hydroxy or aralkylamino) methyl-5- nitroi-midazole by aprocess that comprises dehydration of the latter compounds with silicagel to l-loweralkyl-2- aralkyliminomethyl-S-nitroimidazole, followed byreduction of said latter substance with an alkali metal borohydride orother selective reducing agent. l-lOWCIEilkYl-Z-aralkylaminomethyl-S-nitroimidazole compounds are thus obtained, and maybe isolated by known procedures. Examples of S-nitroimidazolescontemplated by this invention and synthesized in this way arel-methyl-Z-benzylaminomethyl-S-nitroirnidazole andlethyl-Z-benzylaminomethyl 5 nitroimidazole, as well as heteroalkylcompounds such as 1-methyl-2-pyridylmethylarninomethyl-S- nitroimidazoleand 1-methyl-Z-Ihienylmethylaminomethyl-S-nitroimidazole. The aromaticring of the benzyl radical may be substituted with radicals such asloweralkyl, halo, nitro, alkoxy and carboalkoxy.

The l-substituted-2-aminoalkyl-5-nitroimidazole and 1- substituted-Z-substituted-aminoalkyl-S-nitroimidazole compounds of Formulas I and11 above have a significant degree of anti-trichomonal activity and arethus useful in the treatment of trichomoniasis, i.e. T. vaginalisvaginitis. When employed in treating the protozoan diseasetrichomoniasis, they are administered orally, uniformly dis- I persed ina pharmaceutically acceptable carrier vehicle, usually in tablets,capsules, syrups, solutions and the like. Tablets or capsules containingfrom about 100 to about 500 milligrams of active antitrichomonalingredient are quite satisfactory and are prepared by techniques knownto those skilled in the pharmaceutical art. Thus, these dosage formswill contain the normal diluents, excipients, lubricating agents,binders and extenders regularly employed in compounding solid oraldosage forms. The drugs may, if desired, be suspended or dissolved inliquid vehicles designed for oral administration. Alternatively, theymay be administered topically and for this purpose are distributed intopical formulations such as creams and jellies. The antitrichomonalactivity of representative compounds of this invention is set forthbelow. Activity is expressed in terms of effective dose in mg./ kg., asdetermined by the method described in Cuckler, Kupferberg & Millman,Chemotherapeutic and Tolerance Studies on Amino-Nitro ThiazolesAntibiotics and Chemotherapy,

- 10, 540-550, 1955, and represents in vivo activity in mice.

Compounds: Activity (mt/kg.)1-methyl-2-morpholinomethyl-S-nitroimidazole1-methyl-2-piperidinomethyl-S-nitroimidazole 331-methyl-2-cyclopentylarninomethyl-5 nitroimidazole 401-methyl-Z-pyrrolidinylmethyl-S-nitroimidazole 101-methyl-2-methylaminomethyl-5-nitroimidazole 40 The compounds of thisinvention are also effective in controlling enterohepatitis in turkeys.For this purpose they are administered to turkeys mixed with an elementof turkey sustenance, e.g. feed or drinking water. Good control of thedisease is obtained when the imidazole compounds of the invention areincorporated in a turkey feed ration at levels from about 0.003% toabout 0.1% by weight and preferably from about 0.0125 to 0.05% byweight, of the feed. The optimum concentration will depend to a largeextent on the age of the birds, the severity of the infection and theparticular nitroimidazole employed. With these feed levels good controlof the disease is realized with essentially no undesirable side effectsor retardation of growth of the turkeys. When the turkey feed or turkeyration is employed as the carrier vehicle for the nitroimidazolecompounds, it is desirable that the drug be uniformly mixed throughoutthe feed. This is accomplished by first preparing a premix or feedsupplement composition wherein the active ingredient is present inconcentrations from about 1% to about 40% by weight and where thecarrier or diluent is a non-toxic orally ingestable vehicle. It ispreferred that the carrier be a nutritive one, examples of which arecorn distillers dried grains, wheat shorts, wheat middling, soybeanmeal, fermentation residues and corn meal. These supplements or premixesare then uniformly mixed through the turkey ration by conventionaltechniques such as grinding or milling.

A second route of administration is by way of the drinking water of theturkeys. This is preferred when the turkeys are severely infected sincethe birds will normally continue to drink after they have stopped eatingsolid food. Somewhat higher dose levels are employed for the drinkingwater route than for the solid feed method of administration, and levelsof the nitroimidazole compounds in the drinking water of from about0.025% to about 0.1% by weight are quite satisfactory. Some of theamides of the invention are not highly water soluble, and when any suchare used it is desirable to use suspending or emulsifying agents, or tomake a water-soluble form of the drug.

The following examples are given for the purpose of illustration and notby way of limitation.

nitroimidazole according to the above Example1.-I-metl1yl-2-cl1loromethyl-5-nitr0imidaz0le 1.0 gm. (0.0064 M) of1-methyl-2-hydroxymethyl-S- nitroimidazole is dissolved in ml, ofrefluxing benzene. To this hot solution is added 20 ml. of thionylchloride. The solution is warmed on a steam cone for 20 minutes and thenevaporated to dryness in vacuo. The residue of1-methyl-2-chloromethyl-5-nitroimidazole hydrochloride thus obtained isflushed several times with benzene to remove traces of thionyl chloride.(The 1- methyl 2 chloromethyl-5-nitroimidazole hydrochloride prepared inthis manner is suitable for synthetic purposes without furtherpurification.) It is further purified as follows: It is dissolved in 25ml. of water and the solution made slightly alkaline (pH 8-9) withdilute sodium hydroxide and extracted with 3x100 ml. of chloroform. Thechloroform extracts are combined, backwashed with Water and evaporatedin vacuo to dryness to give substantially pure1-methyl-2-chloromethyl-5-nitroimidazole.

The 1-methyl-2-chloromethyl-5-nitroimidazole is characterized as thep-toluene sulfonic acid salt: To a 20% (W/W) solution of the imidazolein chloroform there is added a solution of excess p-toluene sulfonicacid in ether. The 1-methyl-2-chloromethyl-S-nitroimidazole p-toluenesulfonic acid salt precipitates and is recovered by filtration and driedto substantially pure material, MP. 153- 155 C.

When 1 ethyl 2 hydroxymethyl-S-nitroimidazole, 1-propyl-Z-hydroxymethyl-S-nitroimidazole and 1-butyl-2-hydroxytnethyl-S-nitroimidazole are treated with thionyl chlorideaccording to the foregoing procedure, there are obtained 1-ethyl2-chloromethyl-5-nitroimidazole,l-propyl-2-chloromethyl-5-nitroimidazole andl-butyl-Z-chloromethyl-S-nitroimidazole, respectively.

Reaction of the above 1-loweralkyl-2-hydroxymethyl-5 nitroimidazolecompounds with thionyl bromide instead of thionyl chloride, or withaqueous concentrated hydrogen bromide affords the correspondingl-loweralkyl-Z-bromomethyl-5-nitroimidazoles.

Example 2.1-metlzyl-2-chloromelhyI-S-nitroimidazole 3.10 gm. of dry,crystalline 1-methyl-2-hydroxymethyl- 5-nitroimidazole is placed in a250 ml. round bottom flask, and 20 ml. of thionyl chloride is added overa 2 minute period. The reaction mixture is allowed to stand at roomtemperature for about 30 minutes. The excess thionyl chloride is thenremoved by evaporation in vacuo and any residual thionyl chloride isremoved by flushing the residue with 50 ml. of benzene. The solidcrystalline 1 methyl-2-chloromethyl-5-nitroimidazole thus obtained (4.2gm.) is dried under vacuum to remove traces of thionyl chloride.

Example 3.1-methyl-Z-piperidin0methyl-5- nitroimidazole 500 mg. ofl-methyl-2-hydroxymethyl-S-nitroimidazole is converted to thecorresponding 2chloromethyl compound by the method of Example 1. Theresulting lmethyl-2-chloromethyl-5-nitroimidazole hydrochloride isdissolved in 100 ml. of benzene and the resulting solution treated with1.5 ml. of piperidine. The mixture is warmed at 50 C. for 15 minutes andthen evaporated to dryness in vacuo. The resulting oil is diluted with10 ml. of water and made alkaline to pH 10 with sodium hydroxide. Theresulting aqueous solution is extracted with 3X50 ml. of chloroform. Thechloroform extracts are combined and evaporated to dryness in vacuo. Theresidue is dissolved in 5 ml. of chloroform and chromatographed over 15gms. of alumina. The alumina is eluted with chloroform and thechloroform eluates concentrated to dryness to give 1-methyl-2-piperidinomethyl-5-nitroimidazole. The product isrecrystallized from acetone-ether to give material having a meltingpoint of 83-85 C.

Reaction of piperidine with l-ethyl-Z-bromomethyl-S- procedure affords1- ethyl-Z-piperidinomethyl-S-nitroimidazole.

When morpholine, pyrrolidine and N-methyl piperazine are employed inplace of piperidine in the above reaction, the corresponding aminomethylcompounds are formed:

From morpholine, 1 methyl 2 morpholinomethyl-S- nitroimidazole, M.P.l16117 C.

From pyrrolidine, 1-methyl-Z-pyrrolidinomethyl-S-nitroimidazole, M.P.64-65 C.

From N-methylpiperazine,1-methyl-2-N'-methylpiperazinomethyl-S-nitroimidazole, M.P. 9496 C.

Example 4 .J -methyl-2-dimethy1aminomethyl-5 nitroimidazole (A) 500 mg.of l-methyl-2-hydroxymethyl5-nitroimidazole is converted to 627 mg. of1-methyl-2-ch loromethyl- 5 -nitroimidazole hydrochloride by the methodof Example 1.

This l-methyl-2-chloromethyl-S-nitroimidazole hydrochloride is dissolvedin 200 ml. of 1,2-dimethoxyethane and chilled to about 40 C. in a DryIce bath. ml. of liquid dimethylamine is added with stirring and theresulting solution then allowed to Warm to room temperature.

The solvent is then removed by evaporation in vacuo, and the residuedissolved in 20 ml. of water. The solution is made alkaline (pl-I 10)with 2.5 N sodium hydroxide. The aqueous alkaline solution is extractedwith 3X50 ml. of chloroform, and the combined chloroform extracts aredried over sodium sulfate, filtered and concentrated to dryness invacuo.

The l-methyl-2-dimethylaminomethyl-S-nitroimidazole thus obtained isdissolved in a minimum volume of ether and filtered. 600 mg. ofp-toluene sulfonic acid in a minimum volume of ether is added withstirring. The toluene su=1fonic acid salt of1-methyl-2-dimethylaminoethyl-S-nitroimidazole precipitates and isrecovered by filtration (671 mg). It is recrystallized frommethanolether to give substantially pure material, M.P. 188189 C.

(B) When liquid monomethylamine is employed in the above method in placeof liquid dimethylamine, l-methyl- Z-methylaminomethyl-5-nitroimidazoleis obtained. The p-toluene sulfonic acid salt thereof melts at 198200 C.

Reaction of 630 mg. of 1-propyl-2-chloromethyl-5-nitroimidazole with 10ml. of diethylamine according to the foregoing procedure yieldsl-propyl-2-diethylaminomethyI-S-nitroimidazole.

Example 5.1-methyl-2-phthalimidomethyl-S- nitroimidazole (A) 2.2 gm. ofl-1nethyl-2-hydroxymethyl-S-nitroimidazole is converted to 1.75 gm. ofl-methyl-Z-chloromethyl- S-nitroimidazole as previously described.

The chloromethyl compound is then dissolved in 10 ml. ofdimethylsulfoxide and the solution stirred at room temperature While 3.5gm. of potassium phthalimide is added. The mixture is stirred for anadditional one and a half hours at room temperature and then for 30minutes at 60 C.

The reaction mixture is diluted to 150 ml. with water and cooled in anice bath. l-methyl-Z phthalimidomethyl-S-nitroimidazole crystallizes andis recovered by filtration. It is washed Well with water andrecrystallized from acetone-hexane, M.P. 180-l84 C.

(B) 1-methyl-Z-aminomethyl-5-nitroimidazole 200 mg. of1-methyl-Z-phthalimidomethyl-S-nitroimidazole is dissolved in 100 ml. ofwarm methanol. The solution is cooled to room temperature and 10 ml. ofhydrazine hydrate are added. The mixture is stirred at room temperaturefor about 18 hours and then evaporated to dryness in vacuo. Theresulting crystalline solid is suspended in 50 ml. of 2.5 N hydrochloricacid and stirred at 50 C. for 30 minutes. The solution is neutralizedwith 12 N sodium hydroxide and extracted with five 100 ml. portions ofchloroform. The chloroform extracts are combined, dried over magnesiumsulfate and evaporated to dryness in vacuo to give1-methyl-2-aminomethyl-S-nitroimidazole as an oil. This oil is dissolvedin 5 ml. of chloroform, and 350 mg. of p-toluene sulfonic acid in etheris added to the chloroform solution. The p-toluene sulfonic acid salt ofl-methyl-2-aminomethyl-5- nitroimidazole precipitates and is recoveredby filtration. It is recrystallized from methanol to give substantiallypure material, M.P. 231-234 C.

Example 6 1 -m ethy Z-Z-aminomethyl-5-nitr0imidaz0le 286 mg. of1-methyl-2-phthalimidomethyl-5-nitroimidazole is dissolved in 50 ml. ofrefluxing methanol. 0.25 ml. of hydrazine hydrate is added and thesolution refluxed for 3 hours. It is then concentrated to 15 rnl., andallowed to cool. The crystalline material that separates is removed byfiltration and washed with 2x 15 ml. portions of cold methanol. Themethanol washes and the filtrate are combined and evaporated in vacuo todryness. The thus obtained residue is dissolved in 10 ml. of 1.25 Nsodium hydroxide. The aqueous alkaline solution is extracted with 10x20ml. portions of chloroform. The chloroform extracts are combined andevaporated to dryness, in vacuo to givel-methyl-2-aminomethyl-5-nitroimidazole.

This product is dissolved in 5 ml. of chloroform and 350 mg. ofp-toluene sulfonic acid in a minimum amount of ether is added. The1-methyl-2-aminomethyl-S-nitroimidazole p-toluene sulfonic acid saltprecipitates and is collected by filtration. After recrystallizationfrom methanol-ether it melts at 231234 C.

Example 7.-1-methyl-2-anilin0methyl-S-nitroimidazole 1.51 gm. (8.6 mm.)of l-methyl-2-chloromethyl-5-nitroimidazole is dissolved in 50 ml. ofbenzene. 5.0 ml. of aniline is then added with stirring and the solutionallowed to stand at room temperature for /2 hour. The solution is warmedto reflux on the steam cone, and evaporated to dryness in vacuo. Theresulting residue is dissolved in 20 ml. of 1.25 N sodium hydroxide andextracted with 3 15 ml. of chloroform. The chloroform extracts arecombined, filtered, dried and evaporated in vacuo to dryness.

The solid 1-methyl-2-anilinomethyl-S-nitroimidazole thus obtained isdissolved in 50 ml. of 1:1 chloroformether and the solution treated witha small amount of activated charcoal. The solution is filtered,evaporated to-a volume of about 10 ml. and triturated with hexane. Theflask is chilled in the ice bath to complete crystallization of1-methyl-2-anilinomethyl-5-nitroimidazole.

Recrystallization from isopropanol-ether affords pure1-methyl-2-anilinomethyl-S-nitroimidazole 1.95 gm.) M.P. 161-162 C.

Example 8 When the procedure of Example 7 is repeated using equivalentmolar amounts of N-methylpiperazine and cyclopentylamine in place ofaniline, there is obtained, respectively:

l methyl 2-N piperazinomethyl-S-nitroimidazole, M.P. 94-96 C., and1-methyl-2-cyclopentylaminomethyl- S-nitroimidazole. This is a lowmelting solid and is characterized as its p-toluene sulfonic acid salt,M.P. 222-225 C.

Example 9.1-methyl-2- [4- (Z-ketopiperazinyl) methyl] -5-nitr0imidaz0leresidue of l-methyl-Z-[4-(2-ketopiperazinyl)-mcthyl]-5- nitroimidazoleis dissolved in 500 ml. of refluxing acetone and filtered. The acetoneis then distilled off in vacuo to leave 3.55 gm. of crystalline1-methyl-2-[4-(2-ketopiperazinyl) -methyl] --nitroimidazole.

Recrystallization from isopropanol aflords 2.97 gm. of pure 1 methyl 2[4-(2-ketopiperazinyl)-methyl]-5- nitroimidazole, M.P. l87-l88 C.

Example 10.1-(fl-hydi'oxyethyl)-2-m0rph0lin0methyl- S-nitroimidazole 0.8gm. (3.5 mm.) of l-(fl-acetoxyethyl)-2-hydroxymethyl-S-nitroimidazole isdissolved in 50 ml. of benzene. The solution is warmed to reflux and 20ml. of thionyl chloride added. The reaction mixture is refluxed. forfive minutes then evaporated in vacuo to dryness. The residue thusobtained if flushed with benzene and then dried in vacuo to remove anyresidual thionyl chloride. The resultant 1 (Bacetoxyethyl)-2-chloromethyl-5- nitroimidazole hydrochloride is a white,crystalline, hydroscopic substance.

The 1 (B acetoxyethyl) 2 chloromethyl-S-nitroimidazole hydrochloride isdissolved in a minimum volume of benzene. 5.0 ml. of morpholine areadded, and the mixture stirred at room temperature for 45 minutes. Thereaction mixture is then concentrated to dryness in vacuo and theresidue is dissolved in 20 ml. of Water. The aqueous solution is madestrongly alkaline (to pH with aqueous NaOH and extracted with 3 l00 ml.portions of chloroform. The chloroform extracts are combined, filtered,dried and finally evaporated to dryness in vacuo.

The 1 ([3 acetoxyethyl) 2 morpholinomethyl-5- nitroimidazole (687 mg.)thus obtained is an oil containing small amounts of acetyl morpholineand l-(B- hydroxyethyl)-2-morpholin-omethyl 5 nitroimidazole. It isdissolved in 10 ml. of ethanol and 10 ml. of 4 N hydrochloric acid andthe solution refluxed for /2 hour. It is then evaporated in vacuo todryness. The residue is dissolved in 10 ml. of water and neutralizedwith sodium hydroxide. The aqueous solution is extracted with 3X50 ml.portions of ethyl acetate. The ethyl acetate extracts are combined,backwashed with water and evaporated in vacuo to dryness. The residualoil is crystallized from benzene-hexane to give l-(fi-hydroxyethyl) 2m-orpholinomethyl 5 nitroimidazole. Recrystallization frombenzene-hexane affords substantially pure material, M.P. 12l-122 C.

The 1 (,8 acetoxyethyl) 2 hydroxymethyl-5- nitroimidazole employed asstarting material for this experiment is conveniently obtained by aprocess which is not a part of the present invention but which is ratherthe invention of our colleague Janos Kollonitsch, and which is thefollowing:

1.4 g. of 1 (B acetoxyethyl)-5-nitroimidazole, 1.05

- acid, and evaporated to dryness in vacuo.

g. of paraformaldehyde and 5 ml. of dimethylsulfoxide are placed in aglass tube. The tube is sealed and heated at 110 C. for 24 hours. Themixture is then removed and concentrated to dryness in vacuo. Theresidue is extracted with 5 ml. of hot hexane. The hexane-insolublematerial is dissolved in about 10 ml. of benzene. The benzene solutionis concentrated to about a 5 ml. volume, and hexane added slowly toinduce crystallization of 1 (,8 acetoxyethyl) 2 hydroxymethyl 5nitroimidazole. The product thus obtained is recovered by filtration andair dried, M.P. 8890 C. Yield: 81% of theoretical.

l-(li-hydroxyethyl)-2-hydroxymethyl 5 nitroimidazole is obtained byrepeating the above experiment and using as starting materiall-(fi-hydroxyethyl)-5-nitr0- imidazole.

Other l-(CH OAc 2 hydroxymethyl 5 nitroimidazoles, where n is 2, 3 or 4,and Ac is lower-alkanoyl,

e.g. acetyl, propionyl, 'butyroyl, or benzoyl, are obtained leum ether.

in similar fashion from the corresponding 1-(CH OAc- S-nitroimidazoles.

Example 1 1.1-metlzyI-Z-benzylaminomethyl-5- nitroimidazole 0.7 gm. (2.7mm.) of l-methyl-2-(a-hydroxy-u-benzylamino)-methyl 5 nitroimidazole isdissolved in 2.5 ml. of chloroform. This solution is rapidlychromatographed over 20 gm. of silica gel in a short, squat column. Thecolumn is eluted with ether. The ether eluates are evaporated in vacuoand the residue of '1 methyl-2- benzyliminomethyl-S-nitroimidazole isstored at 0-5 C. until just prior to use.

The 1 methyl 2 benzyliminomethyl 5 nitroimidazole is then dissolved in50 ml. of 50% isopropanol methanol and the solution cooled to 05 C.0.150 gm. of sodium borahydride is added with stirring, and the mixtureis stirred and allowed to warm to room temperature over a30 minuteperiod.

The solution is then acidified to pH 5 with hydrochloric The residue isdissolved in 50 ml. of 1.25 N sodium hydroxide and extracted with 3 X100 ml. portions of chloroform.

The chloroform extracts are combined, filtered, dried and evaporated invacuo to dryness. The residue is dissolved in hot hexane, and treatedwhile hot with a small amount of decolorizing charcoal. The charcoal isfiltered off and the hexane solution evaporated, on the steam cone,until it becomes cloudy. The solution is then cooled. .l methyl 2benzylaminomethyl-S- nitroimidazole crystallizes and is recovered byfiltration Recrystallization from isopropanol-hexane yields purematerial, M.P. 73-75 C.

q 157 mg. of 1 methyl 2 hydroxymethyl 5 nitroimidazole and 348 mg. ofactivated manganese dioxide are refluxed together for two hours in 5 ml.of benzene. At the .end of this time the manganese dioxide is removed bycentrifuging and washed with hot benzene. The reaction solution andbenzene washes are added to an equal volume of ether and the solutionpassed through 1 gm. of acid washed alumina. The eluate is concentratedin vacuo to dryness to leave a residue consisting of crystallinel-methyl-2-formyl-5-nitroimidazole, M.P. 98 C.

0.5 gm. of 1 methyl 2 formyl 5 nitroimidazole is dissolved in 50 ml. ofbenzene and the solution cooled and stirred at 15 C. 0.5 ml. ofbenzylamine is added and stirring is continued for about 15 minutes at15-20 C. The resulting crystalline product is removed by filtration,washed with hexane and recrystallized at room temperature fromchloroform by the addition of petro- The crystals of l-methyl-2-(a-hydroxy-abenzylamino)-methyl-5-nitroimidazole thus obtained .meltwith decomposition at 6680 C.

Example 12 ,10 gm. of 1 benzyl 2 hydroxymethylimidazole is heated forabout 15 minutes with 10 ml. of thionyl chloride. The reaction mixtureis-then cooledand the resulting crystalline suspension diluted withabout 10 ml. of ether. The crystalline 1-benzyl-2-chloromethylimidazolehydrochloride is recovered by filtration and washed with ether. It isair dried and 5 gm. of the product treated with ml. of liquid ammoniafor 24 hours in a pressure vessel at room temperature. The excessammonia is then allowed toevaporate and the residual product extractedwith 3X30 ml. of ethyl acetate. The solvent extracts are combined,concentrated in vacuo to an oil which is dissolved in 25 ml. ofconcentrated hydrochloric acid. The acidic solution is evaporated todryness in vacuo and the crystalline residue ofl-benzyl-2-aminomethylimidazole dihydrochloride recrystallized fromethanol-ether to give substantially pure material, M.P. 174- 177 C. Y I

6.4 gm. .of 1-benzyl-2-aminomethylimidazole dihydrochloride is dissolvedin a minimal volume of water and 13 then mixed with 19 ml. of 2.5 Nsodium hydroxide. The resulting mixture is extracted with 3X10 ml. ofchloroform and the combined chloroform extracts dried over magnesiumsulfate and then evaporated to dryness to give1-benzyl-2-aminomethylimidazole. This product is dissolved in about 40ml. of liquid ammonia and the resulting solution treated with 1.6 gm. ofmetallic sodium.

The mixture is stirred for 10 minutes and then a total of 5.8 gm. ofsolid ammonium chloride is added portionwise. The ammonia is allowed toevaporate and the residual product dissolved in 40 ml. of 2.5 N sodiumhydroxide. 80 m1. of tetrahydrofuran is added and the mixture cooled inan ice bath. The resulting cold mixture is stirred and treated drop-wisewith 20 ml. of acidic anhydride. 2.5 N sodium hydroxide is then addeddropwise until the mixture is basic. The reaction mass is then extractedwith 3 50 ml. of n-butanol and the combined butanol extracts evaporatedto dryness. The residue thus obtained is extracted with hot acetone andthe acetone extracts then evaporated to dryness to give crystalline 2acetamidomethylimidazole. Recrystallization from acetone-ether yieldssubstantially pure material, M.P. 183-188 C.

4 gm. of the above product is dissolved in 20 ml. of cold, concetratednitric acid and the solutiontreated dropwise with cooling with 20 ml. ofcold, concentrated sulfuric acid. The resulting mixture is heated at 120C. for one hour and then cooled and poured over 50 gm. of ice. Themixture is then made basic with potassium carbonate, extracted with 30ml. of m-butanol, neutralized with dilute hydrochloric acid and thenextracted with an equal-volume of butanol. The butanol extracts arecombined and concentrated to dryness in vacuo. The residue thus obtainedis extracted with 2x250 ml. of acetone. The acetone extracts areconcentrated to an oil. This oil is triturated with 12 ml. of acetoneand the resulting crystalline 2-acetamidomethyl-4-(or 5 )-nitroimidazolepurified by recrystallization from methanol to give substantially purematerial.

100 mg. of the latter product is heated at 100 C. with 0.06 ml. ofdimethyl sulfate for 70 minutes. The reaction mixture is then cooled andabout 1 cc. of Water added to it. It is then made basic with dilutesodium hydroxide and extracted with 3X3 ml. of chloroform. Thechloroform extracts are dried over sodium sulfate and evaporated todryness in vacuo to give a crystalline residue of1-methyl-2-acetamidomethyl-5-nitroimidazole. Recrystallization fromacetone-ether yields substantially pure material, M.P. 131132 C Examplel3.] methyl-2-(4-hydroxypiperidyl)-me tlzyl- 5-nizr0imialaz0le To asolution of 5.13 gm. of l-methyl-2-chloromethyl- S-nitroimidazole in 100ml. of methanol there is added, with stirring, gm. of sodiumbicarbonatefollowed by a solution of 3.5 gm. of 4-hydroxypiperidine in100 ml. of methanol. The reaction mixture is stirred at room temperaturefor about hours and then evaporated to dryness in vacuo. 100 ml. ofwater is added to the residue and the resulting mixture extracted withfive 100 ml. portions of ethyl acetate. Each ethyl acetate extract isbackwashed with 50 ml. of water. The ethyl acetate solutions are thencombined and evaporated to dryness in vacuo to leave 5.7 gm. of aresidue of 1-methyl-2-(4- hydroxypiperidyl) methyl-S-nitroimidazole.This product is dissolved in about ml. of hot isopropanol, the mixturefiltered and the filtrate concentrated to a volume of 10 ml. Thissolution is cooled, whereupon l-methyl- 2(4-hydroxypipe-ridyl)-methyl-5-nitroimidazole crystallizes. The productis recovered by filtration and dried to yield 4.1 gm., M.P. 139146 C.

The same product is obtained by reacting an equimolar amount of1-methyl-2-bromomethyl-5-nitroimidazole (instead of thechloromethylimidazole) with 4-hydroxypi eridine according to the aboveprocedure.

Example I4.1 methyl 2-allylamin0-5-nitroimidazole 475 mg. of1-methyl-2-chloromethyl-S-nitroimidazole is dissolved in 10 ml. ofbenzene. 1 ml. of allylamine is added to the benzene solution and themixture warmed to the reflux temperature and refluxed for five minutes.It is then evaporated in vacuo to an oil and the oil is dissolved in 10ml. of saturated aqueous potassium bicarbonate. The solution isextracted with three 25 ml. portions of chloroform. The chloroformextracts are combined, backwashed with 10 ml. of water, dried overmagnesium sulfate and then evaporated in vacuo to an oil. The residue of1-methyl-2-allylamino-5-nitroimidazole is dissolved in 5 ml. ofchloroform and to this solution there is added 500 mg. of p-toluenesulfonic acid in 12.5

ml. of chloroform; The white crystalline product that forms is removedby filtration and recry-stallized'from methanol to give substantiallypure l-methyl-Z-allyl amino-S-nitroimidazole p-toluene sulfonic acidsalt, M.P. 193196 C. When 1-ethyl-2-chloromethyl-5-nitroirnidazole isemployed in the above experiment instead of 1-methyl-2-chloromethyl-5-nitroimidazole there is obtained the p-toluenesulfonic acid salt of 1-ethyl-2-allylamino-5- nitroimidazole.

Example I5.I -metl1yl-2-(1 '-imidaz0lyl) -methyl-5-nitr0- imidazole To1.01 gm. of 1-methyl-2-chloromethyl-S-nitroimidazole there is added 5gm. of imidazole, the mixture is warmed and stirred util the imidazolemelts. It is then heated at 140 C., with stirring, for 20 minutes and atthe end of this time poured into 100 ml. of water. To theresulting'solution there is added 3.5 gm. of sodium bicarbonate and theentire mixture is then extracted with five 200 ml. portions of ethylacetate. The ethyl acetate extracts are separately backwashed with 50ml. of water and then combined and dried over sodium sulfate. The sodiumsulfate is removed by filtration and the ethyl acetate solution treatedat room temperature with 1 gm. of decolorizing charcoal. The charcoal isthen removed by filtration and the filtrate evaporated to dryness invacuo to give 850mg. of 1-methyl-2- (1'-imidazolyl)-methyl-5-nitroimidazole. This product is dissolved in 15 ml. of isopropanol andthe solution concentrated to a volume of about 3 ml. It is then filteredand the filtrate cooled whereupon 1methyl-2-(1'-imidazolyl)-methyl-5-nitroimidazole crystallizes. Theproduct is recrystallized from isopropanol to yieldsubstantially purematerial, M.P. 99101 C. i

Example 16.-1-metlzyl-2-m0rplzolinomethyl-S- nitroimidazole To 15.6 gm.of .1methyl-2-hydroxymethyl-S-nitroimidazole in a 500 ml. flask there isadded over a three minute period 50 ml. of thionyl chloride. The mixtureis warmed to 50 C. for 30 minutes and at the end of this time the excessthionyl chloride is evaporated in vacuo. The residue is flushed with 50ml. of benzene. It is then cooled to about room temperature and 100 ml.of water added. The mixture is made alkaline with 2.5 N sodium hydroxideand the aqueous alkaline solution extracted with five 150 ml. portionsof chloroform. Each chloroform extract is backwashed with 50 ml. ofwater. The chloroform extracts are then combined and evaporated todryness in vacuo to afford 17.3 gm. of l-rnethyl-Z-chloromethyl-S-nitroimidazole. This product is dissolved in 500 ml. ofbenzene and a solution of 40 ml. of morpholine in 100 ml. of benzene isadded. The mixture is stirred at room temperature for one hour and thenwarmed to C. for about 5 minutes. It is then evaporated in vacuo todryness. The residue is dissolved in 150 ml. of water and 50 ml. ofsaturated aqueous potassium bicarbonate solution is added. The resultingsolution is extracted with five 200 ml. portions of chloroform, thechloroform extracts each washed with m1. of water and then evaporated todryness in vacuo. There is obtained 1 methyl2-morpholinomethyl-5-nitroimidazole which on recrystallization fromchloroform yields 20 gm. of substantially pure material, M.P. 1l8119 C.

Example 1 7.-N-carbamyI-1-methyI-Z-aminomethyl- 5-nirroimidaz0le To 463gm. of 1-methyl-2-aminomethyl-5-nitroimid azole in 5 ml. of ethanol isadded 325 ml. of nitrourea in 5 ml. of 50% aqueous ethanol. The mixtureis warmed gently on a steam bath for one hour and then evaporated todryness on a steam bath in a nitrogen atmosphere. The residual productis dissolved in 2 ml. of methanol. It is chromatographed over 25 gm. ofsilica gel prepared in hexane. The column is Washed successively with200 ml. of chloroform, 50 ml. of chloroform containing 5 volume percentmethanol, 50 ml. of chloroform containing 10 volume percent of methanol,and 85 ml. of chloroform containing 20 volume percent of methanol. Thechloroform20% methanol eluate is collected and evaporated to dryness invacuo to give a residue of N'- carbamyl1-methyl-2-aminomethy-l-S-nitroimidazole. On recrystallization fromisopropanol the product (340 mg.) melts at l65170 C.

Example I8.N- I-metlzyl-5-nitr0-2-imiclazolylmethyl) -v-pyridne 2.0 g.of 1-methyl-2-chloromethyl-5-nitro-irnidazole is dissolved in 10 ml. ofdimethylforma-mide, and this solution added over a period of 10 minutesto a solution of 1.10 g. of 'y-pyridone in 10 ml. of dimethylformamidepreviously treated with 535 mg. of 52% sodium hydride in oil. Themixture is stirred at room temperature for 2 hours and then diluted with80 ml. of water. The mixture is extracted with three 50 ml. portions ofmethylene chloride. The methylene chloride extracts are combined, driedover Na SO and evaporated to dryness in vacuo toleave a residue of crudeN-(l-methyl-S-nitro-Z-imida'zolylmethyl)-'y-pyridone. The product ispurified by recrystallization from isopropanol...

Example 19 When the procedure of Example 16 is repeated usingthiamorpholine in place of morpholine,1-methyl-2-thiamorpholinomethyl-S-nitroimidazole is obtained. Similarly,when 1-methyl-2-(u-hydroxyethyl)-5-nitroimidazole is reacted withthionyl chloride by the proced- -ure of Example 1, there is producedI-methyI-Z-(wchloroethyl)5-nitroimidazole. On treatment of thissubstance with a molar excess of morpholine under the reactionconditions of Example 16, 1-methyl-2-(a-morpholinoethyl)-S-nitroimidazole is produced.

In addition to those described in Example 10, the starting materialsused in carrying out the processes and making the compounds of thisinvention are prepared in the following manner:

(a) 1-10weralkyl-2Jrydroxymet/zyl-5-nitroimidaz0le 83.0 gm. (0.864 M) of2-hydroxymethyl imidazole is dissolved in 200 ml. of acetic anhydride.The solution is allowed to stand overnight at room temperature. Theacetate salt of 2-acetoxymethyl imidazole crystallizes. The crystallinesolid is slurried well with ether, filtered :and the crystals are washedwith ether until the odor of acetic acid is no longer detectable. TheZ-acetoxymethyl imidazole acetic acid salt melts at 80 C. The 2-acetoxymethyl imidazole acetic acid salt is dissolved in :sodium bicarbonateand the 2-acetoxy-methyl imidazole extracted with. ethyl acetate.Evaporation of the ethyl acetate extracts, in vacuo, andrecrystallization of the residue from ethyl acetate affords2-acetoxymethyl imidazole, M.P. 82-85 C.

176.6 gm. (0.882 M) of 2-acetoxymethyl imidazole acetic acid salt isadded in small amounts to 165 ml. of cold, fuming 90% nitric acid. Thissolution is added slowly with stirring and cooling to 150 ml. of cold,fuming 9.0% nitric acid containing 90.1 gm. of gaseousBF The reactionmixture is heated on the steam cone for five hours.

After cooling to room temperature, the reaction mixture is poured overice and neutralized with sodium hydroxide. The resulting solution isthen extracted with ethyl acetate, and the ethyl acetate extractsevaporated, in vacuo, to dryness. The residue is refluxed for one hourin a solution of 100 ml. of 2.5 N sodium hydroxide and 100 ml. ofmethanol. The solution is then neutralized with hydrochloric acid andextracted with ethyl acetate. The extracts are evaporated to dryness,dissolved in methanol and chromatographed over charcoal.

Elution of the charcoal with 50% ether-acetone first removes a smallamount of imidazole-Z-carboxaldehyde. The next substance eluted is2-hydroxymethyl-4(5)-nitroimidazole. After recrystallization fromacetone, this melts at 156158 C.

12.6 gm. of dimethyl sulfate is added to 11.1 gm. of 2-hydroxymethyl-4(5)-nitroimidazole and the mass throughly mixed. The massis then heated on the steam cone for two hours and cooled to roomtemperature.

A small amount of ice is added, and the remaining dimethyl sulfate andmethyl hydrogen sulfate neutralized by slow addition of concentratedammonium hydroxide. The resulting solution is extracted with chloroform.The

I chloroform extracts are separated and evaporated to dry- 7 water.

ness to yield a residue consisting of1-methyl-2-hydroxymethyl-S-nitroimidazole. Recrystallization fromacetone affords substantially pure 1-methyl-2-hydroxymethyl-5-nitroimidazole, M.P. 117-1 19 C.

When the above reaction is carried out using diethyl sulfate ordipropylsulfate in place of dimethyl sulfate, there is obtained respectively1-ethyl-2-hydroxymethyl-5- nitroimidazole and l-propyl-2-hydroxymethyl 5nitroimidazole.

(b) I-l0weralkyl-2-(a-hydroxyalkyl)-5-nitroimidazoles 5 gm. of1,2-dimethyl-5-nitroimiclazole (0.035 M) and 18 ml. of benzaldehyde(0.18 M) are added to a mixture of 90 ml. of absolute ethanol and 6 gm.of potassium t-butoxide (0.054 M). The resulting mixture is heated at 75C. in a water bath for 20 minutes. It is then cooled in an ice bath andthe solid precipitate of l-methyl- 2-(B-phenyl-vinyl)-5-nitroimidazoleremoved by filtration. The solid is washed first with ethanol and thenwith The remaining crystalline product is l-methyl-2-(B-phenyl-vinyl)-5-nitroimidazole, M.P. 198-199" C. after air drying.

40 gm. of 1-methyl2-(fi-phenyl-vinyl)-5-nitroimidazole and gm. of sodiumperiodate are added to a mixture of 800 m1. of 1,2-dimethoxyethane and200 ml. of water at room temperature. 1 gm. of osmium tetroxide is thenadded and the mixture stirred for 17 hours at room temperature. The paleyellow reaction mixture which contains a heavy white precipitate ispoured into 6 l. of water and the entire mixture extracted with three1300 ml'. portions of chloroform. The chloroform extracts are combined,dried over sodium sulfate and concentrated to dryness in vacuo to abrown oil. This oil crystallizes on cooling. The resulting crystallineresidue is extracted with four 200 ml. portions of hot ethyl ether. Theether extracts are combined and diluted with an equal volume of hexane.The resulting solution is chromatographed over a column of 350 gm. ofacid washed alumina prepared in 1:1 ether-hexane. The column is elutedwith 1:1 ether-hexane to remove a colorless fraction containing 8.2 gm.of an oil having the odor of benzaldehyde. The column is then elutedwith about 1.5 l. of ether and this eluate concentrated to a volume ofabout 350 ml. It is allowed to stand at room temperature for about 12hours during which time about 4.1 gm. of l-methyl-Z-formyl-S-nitroimidazole crystallizes. The product is recovered byfiltration and dried, M.P. -98 C.

500 mg. of 1-methyl-2-formyl-S-nitroimidazole in 20 ml. of dry ether istreated with one equivalent of methyl 17 magnesium iodide in 17.8 ml. ofether. After refluxing for 15-20 minutes, 15 ml. addition ether and 6.7ml of 0.5 N hydrochloric acid are added. This mixture is warmed briefly,cooled and the phases separated. The ether phase is dried over Na SO andtaken to dryness in vacuo to leave 271 mg. of crude 1-methyl-2-(oc-hY-droxyethyl)-5-nitroimidazole. This is recrystallized once fromether-petroleum ether to give purified material. It is further purifiedby passage (in ethyl acetate) through acid washed alumina.

Example 20 When the compounds of this invention are used for thetreatment of trichomoniasis, they are generally compounded into suitablepharmaceutical formulations which include compressed tablets, coatedtablets, capsules, suspensions or solutions for oral administration, andvaginal creams or suppositories for topical application. A typicalexamples of a compressed tablet is:

Mg. per tablet l-methyl-2amorpholinomethyl-S-nitroimidazole 250Dicalcium phosphate 100 Lactose 75 Starch 50 Guar gum 12 Magnesiumstearate 2 The imidazole is uniformly mixed with the other componentsand the mixture then compressed into tablets. The ingredients of thetablets may be varied using a diluent (instead of dicalcium phosphate orlactose) such as kaolin, calcium sulfate, sucrose or sorbitol; agranulating agent (in place of starch) such as gum acacia or gumtragacanth; a disintegrant such as dried starch or cellulose (in placeof guar gum); and a lubricant such as tak or stearic acid (in place ofmagnesium stearate). In addition, other S-nitroimidazoles describedherein may be substituted for the1-methyl-2-morpholinomethyl-5nitroimidazole used in the foregoingexample.

Tablets may be sugar coated by applying a heavy sugar syrup, or entericcoated by spraying with a material such as cellulose acetate phthalate.

Capsules are prepared by blending the antitrichomonal agent with afiller such as starch, lactose or kaolin, and lubricating with calciumor magnesium stearate before encapsulation. A typical capsule has thecomposition:

Mg. 1-irnethyl-Z-thiamorpholinomethyl-S-nitroimidazole 25 Calciumstearate 2 Lactose, to fill No. capsule, ca 75 For vaginal creams thenitroimidazole compound is blended with sufficient quantities ofhydrophilic ointment and water to give a cream of the desiredconsistency and containing 10% by weight of the imidazole. For vaginalsuppositories, from 100-500 mg. of nitroimidazole compound of theinvention is blended with about grams of theobroma oil U.S.P. or amixture of polyethylene glycols.

18 Any departure from the above description which conforms to thepresent invention is intended to be included Within the scope of theclaims.

What is claimed is: 1. A 5-nitroimidazole of theformula ozN LN lax lwhere X represents halogen having an atomic weight greater than 35 andless than 130, and A and R are each loweralkyl; and acid addition saltsthereof.

3. 1-methyl-2-chloromethyl-5-nitroimidazole.

4. l-methyl-Z chloromethyl 5 nitroimidazole hydrochloride.

5. l-(fl-acyloxyethyl)-2-chl0romethy1-5 nitroimidazole wherein the acylgroup is lower alkanoyl or benzoyl.

6. l-(B-acetoxyethyl)-2-chloromethyl-5-nitroimidazole.

References Cited by the Examiner UNITED STATES PATENTS 2,160,293 5/1939Shoemaker 260--309 2,404,299 7/1946 Kyrides 260309 2,603,649 7/1952C-lapp 260309 2,852,515 9/1958 Elpern 260-247.5 2,953,492 9/1960 Duggins260309 3,037,028 5/1962 Green 260309 3,056,705 10/1962 Wong 2603093,132,151 5/1964 Bortnick 260-313 OTHER REFERENCES Fieser et al.:Organic Chemistry 2nd ed., pages 147-8, Boston, Heath, 1950.

Jocelyn Jour. Chem. Soc. (London) 1957, pages 3305-6.

Kimijiima et al.: Chemical Abstracts, vol. 43, pages 20212 (1949).

Schneider et al.: Hoppe-Seylers Zeit, Physiol. Chem, vol. 327, page 76(1962).

WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

N- TROUSOF, A i tan Exam ner.

1. A 5-NITROIMIDAZOLE OF THE FORMULA